AstraZeneca Presents Further Evidence for the Potential of AZD9291 in First-Line and Pre-Treated Non-Small Cell Lung Cancer

“AstraZeneca today announced updated data on AZD9291 in first-line patients with epidermal growth factor receptor mutation (EGFRm) positive advanced non-small cell lung cancer (NSCLC) and previously-treated patients with EGFRm T790M mutation-positive NSCLC. The data being presented today at the World Conference on Lung Cancer (WCLC) 2015 were from the AURA Phase I trial first-line cohort and two AURA Phase II studies.

“Data demonstrated that in 60 patients who received AZD9291 once daily in the first-line setting, 72% (95% confidence interval (CI) 58% to 82%) were progression free (PFS) at 12 months. Confirmed overall response rate (ORR) was 75% (95% CI 62% to 85%). The longest duration of response (DoR) was ongoing at 18 months.

“ ‘While the data are still preliminary, these latest results from the AURA trial first-line cohort further reinforce the potential of AZD9291 in treatment-naïve EGFRm advanced NSCLC patients,’ said Professor Suresh S. Ramalingam, presenting author of the AURA trial first-line cohort data and Chief of Thoracic Oncology and Director of Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.”


Clovis Completes Rociletinib NDA for EGFR T790M-positive NSCLC

“A new drug application (NDA) has been submitted for rociletinib (CO-1686) as a treatment for patients with EGFR T790M-positive metastatic non–small cell lung cancer (NSCLC) following prior administration of an EGFR TKI, according to a statement from the drug’s developer, Clovis Oncology.

“The NDA was preceded by a breakthrough therapy designation for the potent mutant-selective EGFR inhibitor in May 2014. The application was based on findings from the ongoing phase I/II TIGER-X trial, which were published in The New England Journal of Medicine and updated at the 2015 ASCO Annual Meeting. In patients with T790M-mutant NSCLC by tissue testing (n = 243), the objective response rate (ORR) across all dose levels was 53% and the disease control rate (DCR) was 85%.

“An application for premarket approval (PMA) is anticipated for Qiagen’s therascreen EGFR RGQ PCR Kit as a companion diagnostic (CDx) for rociletinib, according to the statement. The therascreen EGFR test was initially approved in 2013 as a CDx for afatinib (Gilotrif) and recently received a new indication as a CDx for gefitinib (Iressa).”


Biodesix Launches GeneStrat Targeted Liquid Biopsy Mutation Test For Patients With Advanced Lung Cancer

“Biodesix, Inc. today announced the launch of GeneStrat™, a targeted liquid biopsy mutation test for genotyping tumors of patients with advanced non-small cell lung cancer (NSCLC). The blood test results are available within 72 hours, providing physicians actionable diagnostic information prior to making treatment decisions. GeneStrat is focused exclusively on the clinically actionable EGFR, KRAS, and BRAF mutations often used to guide targeted therapy treatment decisions. GeneStrat also captures the EGFR T790M mutation, which can be used for monitoring the emergence of the primary resistance mutation in the EGFR gene. It is anticipated that two drugs targeting the resistance mutation may be available later this year. GeneStrat uses the ddPCR platform to analyze cell-free tumor DNA and is highly concordant with tissue analysis, currently considered the gold standard.

“Roughly 30% of lung cancer patients either have insufficient biopsy tissue or are not candidates for a biopsy for tumor mutation profiling. Even in cases where tissue biopsy is available, the sense of urgency to treat is great, with one recent study showing that one out of four patients begin cancer treatment before receiving mutation test results. Requiring only a blood draw, GeneStrat offers a fast, minimally invasive alternative to a high-risk tissue biopsy or re-biopsy in patients with insufficient tissue.

“In addition to providing a minimally-invasive source of mutation status, liquid biopsy can be more cost-effective than traditional tissue biopsies. The mean cost of each tissue biopsy is $14,634 across all patients. The cost of a tissue biopsy can be up to four time higher in the 19.3% of patients who have complications associated with the biopsy. GeneStrat liquid biopsy can help avoid the cost and complications of repeat tissue biopsy.”


Clovis Oncology's Rociletinib (CO-1686) Phase 2 Study Results Demonstrate Consistent and Promising Clinical Activity and Disease Control in Very Advanced Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

“Clovis Oncology (NASDAQ:CLVS) announced today updated findings from its Phase 2 clinical study of rociletinib (CO-1686), the Company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M. These data from the TIGER-X trial are being presented today in an oral presentation (Abstract #8001) at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

“ ‘The maturing data for rociletinib confirm in a large patient population what we have seen in our early clinical experience,’ said Jonathan Goldman, MD, TIGER-X investigator and Assistant Professor, UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology. ‘Rociletinib has shown very encouraging and durable activity in the most advanced mutant EGFR lung cancer patients, including in a large population of patients with CNS metastases. Importantly, the data continue to show activity in both T790M-positive and T790M-negative patients, which gives us a potential treatment option for all patients who have progressed on their initial EGFR targeted therapy.’ “


AZD9291 Shows Durable Responses in Patients With EGFR-Positive Lung Cancers

“A clinical trial of the EGFR inhibitor AZD9291 in patients with advanced non–small cell lung cancer (NSCLC) who had disease progression after previous treatment with EGFR tyrosine kinase inhibitors has found that the drug was highly active—achieving a 95% disease control rate—in patients with the EGFR T790M mutation. The median progression-free survival was 9.6 months in the EGFR T790M–positive patients, and 2.8 months in EGFR–negative patients. Why the drug is less effective in patients whose cancers lacked the T790M mutation is unclear. The study by Jänne et al is published in The New England Journal of Medicine.

“A total of 253 patients were enrolled in the study. The researchers administered AZD9291 at doses of 20 mg to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors.

“The study included dose-escalation cohorts and dose-expansion cohorts; prestudy tumor biopsies were required for central determination of EGFR T790M status in the expansion cohorts. Patients were assessed for safety, pharmacokinetics, and efficacy.”


EGFR Inhibitor Rociletinib Active in EGFR T790M Mutation–Positive NSCLC Previously Treated With EGFR Inhibitors

“In a phase I/II study reported in The New England Journal of Medicine, Sequist et al found that rociletinib—an EGFR inhibitor active in the presence and absence of the EGFR T790M mutation known to mediate resistance to available EGFR inhibitors—produced a high response rate in patients with T790M-positive non–small cell lung cancer (NSCLC) who had progressed on prior EGFR inhibitor therapy. Responses were also observed in patients with T790M-negative disease.

“The study included 92 evaluable patients with EGFR-mutant NSCLC that had progressed on treatment with an EGFR inhibitor who were treated with a free-base form of rociletinib (first group of enrolled patients) at a dose of 900 mg twice daily (10 with centrally confirmed presence or absence of T790M mutation) or a hydrogen bromide salt form at doses of 500 mg twice daily to 1,000 mg twice daily (all remaining patients; 53 with centrally confirmed presence or absence of T790M mutation).

“A total of 83 patients were evaluable for response. Among 46 patients with centrally confirmed T790M-positive tumors, 59% (95% confidence interval [CI] = 45%–73%) had a partial response, and 35% had stable disease (disease control rate = 93%). Response rates were similar in patients with deletion 19 or L858R EGFR mutations. Estimated median progression-free survival at the time of analysis was 13.1 months (95% CI = 5.4–13.1 months), with data censored for 82% of patients. Among 17 patients with T790M-negative tumors on central testing, the response rate was 29% (95% CI = 8%–51%), and 29% had stable disease (disease control rate = 59%). Estimated median progression-free survival in these patients was 5.6 months (95% CI = 1.3 months to not reached). Among 20 patients whose tumors were not assessable for T790M mutation, the response rate was 15%.”


Two New Drugs for EGFR+ Lung Cancer That Has Progressed

“Two new drugs for a specific lung cancer scenario are approaching the market –― AZD9291 (AstraZeneca Pharmaceuticals LP) and rociletinib (Clovis Oncology), and both companies are preparing to file for approval.

“Both drugs are third-generation EGFR inhibitors destined for use in patients who have non–small cell lung cancer (NSCLC) that is EGFR-mutation-positive and has responded to treatment with first-line EGFR inhibitors, but is now progressing.

“In about 60% of these cases, the disease is progressing because the tumor has developed a new mutation, known as EGFR T790M. This mutation confers resistance to treatment with first- generation EGFR inhibitors, such as erlotinib (Tarceva, Osi Pharmaceuticals, Inc) and gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) or the second-generation EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc).”


Lung Cancer Pioneer Thomas Lynch Discusses the State of the Art

“Thomas Lynch, MD, has been a leader in the development of numerous novel therapies for the treatment of lung cancer. His significant contributions to the field have earned him great recognition, including the 2013 Giants of Cancer CareTM award in Lung Cancer for his pioneering use of molecular testing for EGFR mutations.

“Lynch, who is director of the Yale Cancer Center and physician-in-chief at the Smilow Cancer Hospital at Yale-New Haven, recently sat down with OncLive and discussed key strategies and trends in the management of lung cancer. In a wide-ranging interview, Lynch provides expert insight across the spectrum of care, from screening to the challenges associated with resistance mutations.”


A Blood-Based Test for EGFR Mutations in NSCLC Is Being Developed

“Clovis Oncology is evaluating a blood-based assay to detect EGFR mutations in circulating tumor DNA in non-small cell lung cancer patients as a way to better identify candidates for treatment with rociletinib (CO-1686), its investigational EGFR inhibitor, a Clovis scientist said this week.

“During a talk at the Cambridge Healthtech Institute Molecular Medicine Tri-Conference held here, Chris Karlovich, principal scientist for molecular diagnostics at Clovis, said that his company is comparing the performance of Sysmex Inostics’ BEAMing assay service to that of Qiagen’s TheraScreen EGFR PCR test in a subset of patients from the company’s “third-generation inhibitor of mutant EGFR lung cancer” (TIGER) clinical trial for rociletinib.

“The goal, Karlovich said, is to overcome some of the limitations of tissue-based PCR testing in identifying EGFR mutations, particularly the T790M resistance mutation, which can be used to identify patients who have become resistant to EGFR-directed therapy and thus are candidates for second- or later-line treatment with rociletinib. In addition, Karlovich said, blood-based assays like BEAMing could potentially be used to more easily monitor response to the drug.

“Rociletinib was designed to selectively target initial activating EGFR mutations and the T790M resistance mutation, while sparing wild-type EGFR at anticipated therapeutic doses, with an improved toxicity profile, according to Clovis’ website.”